O-Glycosylation of Nuclear and Cytoplasmic Proteins: Regulation Analogous to Phosphorylation?

Haltiwanger, Robert S.; Busby, Scott A.; Grove, Kathleen; Li, Sean; Mason, Doug; Medina, Lillian; Moloney, Daniel J.; Philipsberg, Glenn A.; Scartozzi, Richard

doi:10.1006/bbrc.1997.6110

Cited by 92 publications

(64 citation statements)

References 68 publications

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“…Although GalNAc shows a more dramatic influence on the coil (or ␣)-to-␤ structural conversion of the prion peptide, the effects associated with this sugar are probably not physiological. In contrast, the fact that O-GlcNAc glycosylation has been found in many proteins, including the tau protein and the ␤-amyloid precursor membrane protein related to the neuron degenerative Alzheimer's disease, emphasizes the physiological significance of GlcNAc (25)(26)(27)(28). O-linked GalNAc generally occurs in mucin-type glycoproteins that contain repeating units of Ser, Thr, and Pro in short regions of the peptide chain (29).…”

Section: Discussionmentioning

confidence: 99%

One O-linked sugar can affect the coil-to-β structural transition of the prion peptide

Chen

Lin

Chang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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It has been known that the structural transition from PrP C to PrP Sc leads to the prion formation. This putative conformational change challenges the central dogma of the protein folding theory-''one sequence, one structure.'' Generally, scientists believe that there must be either a posttranslational modification or environmental factors involved in this event. However, all of the efforts to solve the mystery of the PrP C to PrP Sc transition have ended in vain so far. Here we provide evidence linking O-linked glycosylation to the structural transition based on prion peptide studies. We find that the O-linked ␣-GalNAc at Ser-135 suppresses the formation of amyloid fibril formation of the prion peptide at physiological salt concentrations, whereas the peptide with the same sugar at Ser-132 shows the opposite effect. Moreover, this effect is sugar specific. Replacing ␣-GalNAc with ␤-GlcNAc does not yield the same effect.T he prion protein (PrP, 254 aa for hamster PrP) has been found to be associated with the prion infectivity. The normal product of the prion gene is expressed as a glycophosphatidyl inositol-anchored glycoprotein on the outer cell membrane (1-3). The solution NMR structure of recombinant syrian hamster prion protein rPrP(90-231) was determined in 1997 (4). The secondary structure consists of three ␣-helices (144-153, 172-194, 200-227) interdispersed between two short ␤-strands (129)(130)(131)(161)(162)(163); the N terminus (90-111) is largely unstructured ( Fig. 1). A posttranslational process that converts the cellular prion protein (PrP C ) to the abnormal, insoluble, pathogenic isoform (PrP Sc ) has been implicated in the prion formation during the development of prion diseases.CD spectroscopy and Fourier transform infrared spectroscopy studies have indicated that approximately half of the ␣-helical and coiled structure in PrP C is transformed into ␤-sheet in PrP Sc (5). However, the thermodynamics of the ␣-to-␤ transition, including the factors that influence it, remain unknown. PrP C has a high turnover rate in vivo. This high turnover makes the purification of PrP C extremely difficult (6). The low yield of purified PrP C from animal brains or low level of expression in mammalian cells as well as the insolubility of PrP Sc have remained a bottleneck in prion research. It has been difficult to discern whether there are chemical modifications in PrP C that are absent in PrP Sc or vice versa. Although Edman sequencing data suggest that the amino acid sequence of PrP Sc is identical with the translational product of the prion gene (7), we cannot rule out the possibility of low levels of unidentified chemical modifications in PrP C or PrP Sc as the culprit of the medical malady. To date, the search for differential modifications between PrP C and PrP Sc has focused on the two N-linked glycosylation sites at N181 and N197. However, based on the results of tunicamycin treatment, an N-linked glycosylation inhibitor (8), as well as experiments on the expression of unglycosylated mutated prion prot...

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Section: Discussionmentioning

confidence: 99%

One O-linked sugar can affect the coil-to-β structural transition of the prion peptide

Chen

Lin

Chang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…The most common involves the addition of a tritiated UDPGlcNAc ( 3 H-UDP-GlcNAc) to a peptide substrate (Haltiwanger et al 1997). Recently, an effective fluorescencebased substrate analogue displacement assay was developed to assess the activity of OGT (Gross et al 2005).…”

Section: O-glcnac Transferasementioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

119

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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“…O-GlcNAc is a regulatory posttranslational modification more analogous to phosphorylation than to other types of glycosylation (23)(24)(25)(26). In some cases, O-GlcNAc competes with phosphorylation at specific sites (27)(28)(29)(30), and a reciprocal relationship between phosphorylation and O-GlcNAc has been observed globally (31,32).…”

mentioning

confidence: 99%

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes

Vosseller

Wells

Lane

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

432

393

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O-Glycosylation of Nuclear and Cytoplasmic Proteins: Regulation Analogous to Phosphorylation?

Cited by 92 publications

References 68 publications

One O-linked sugar can affect the coil-to-β structural transition of the prion peptide

One O-linked sugar can affect the coil-to-β structural transition of the prion peptide

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes

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